Nicotinic acid (niacin) is a B vitamin with potent hypolipidemic effects. Niacin administration has been related to a reduction in coronary heart disease mortality and overall mortality after recovery from myocardial infarction. Despite its efficacy, however, the clinical use of niacin has been greatly limited by its side effects, the most common of which is intense flushing. Convincing evidence has previously been obtained that flushing after niacin ingestion is prostaglandin (PG) mediated. However, the PG responsible had not been established. We recently found that ingestion of niacin in humans selectively results in 400-800 fold increases in the endogenous release of the prostaglandin, PGD2, a potent vasodilator. These findings strongly implicate PGD2 as the mediator of niacin induced flushing. The overall goals of the proposed studies are to further explore the biochemical pharmacology of niacin in relationship to arachidonic acid metabolism. Data recently obtained by others and results of preliminary experiments we have carried out have formed the basis for the hypothesis that resident tissue macrophages may be the primary source of niacin-induced release of PGD2 in vivo. The specific aims, therefore, will be to (1) examine the hypothesis that resident tissue macrophages in the liver, skin and spleen are the major cellular source of niacin-induced release of PGD2 in vivo, (2) examine whether niacin also evokes the release of leukotrienes in vivo and the release of leukotrienes, and other cellular mediators in vitro, (3) examine potential cellular mechanisms involved in niacin-induced activation of arachidonic acid metabolism, and (4) investigate the possibility that arachidonic acid metabolites may modulate the lipid-lowering properties of niacin. During Phase I of the Physician Scientist Award (years 1-2), the candidate will work under close supervision with the sponsor, L. Jackson Roberts, M.D., Professor of Pharmacology and Medicine. Phase I will be a period of didactic classroom and basic research training. Phase II of the award (years 3-5) will be a period of intensive laboratory research training devoted to the studies outlined in the application. During this period, the candidate will perform the proposed research in a more independent capacity compared to Phase I, although continuing under the supervision of the sponsor.